Novel Delivery Systems of Zotepine – Preparation, Chara-cterization and Comparative in vitro and in vivo Evaluation of Lipid Nanoemulsion and Liquisolid Formulation

Background: Zotepine is a drug for schizophrenia. It has low oral bioavailability (BA) (7-13%) due to poor aqueous solubility, extensive first pass metabolism and efflux of pgp. Purpose of the study: To develop zotepine lipid nanoemulsion (LNE) and liquisolid formulation (LSF) and to compare the oral BA of zotepine from LNE, LSF, and coarse suspension (CS) in wistar rats. Research rationale: Till now, the development of LNE delivery system and BA of zotepine LSF are not reported. Both formulations can improve oral BA. General methods: LNEs were prepared by hot homogenization followed by ultrasonication. Formulations were prepared by varying the concentrations of lecithin. The LNEs were characterized for particle size, PDI, zeta potential, entrapment efficiency, drug content, in-vitro drug release. Physical stability upon centrifugation, autoclaving, dilution and storage was tested. LSFs were prepared with zotepine solution in PEG-200 and mixed with four carriers and aerosil-200, a coating material. The LSFs were evaluated for flow properties, drug content and in vitro dissolution. Pharmacokinetic (PK) study was conducted on optimized F2-LNE, ZSLSF-1 and CS after oral administration in wistar rats and compared their PK parameters. Results: The in-vitro characterization of all formulations were done. The optimized LNE and LSF showed 2.569, 1.079 -fold improvements of BA than that of CS. The F2-LNE showed 2.37-fold improvement in BA over that of LSF. Although ZSLSF-1 showed improvement in dissolution but no significant improvement in oral BA was observed at p˂0.05. This could be due to extensive first pass metabolism. In contrast, F2-LNE showed increased BA over CS, ZSLSF-1 probably due to uptake of drug by lymphatic transport, avoiding the first pass effect. Conclusion: The comparative PK study of optimized F2-LNE, LSF and CS of zotepine indicated the superiority of designed LNE. Accordingly, F2-LNE can be developed as a commercial product.